6-(Lower alkoxy)-5-(trifluoromethyl)-1-naphthalenecarboxylic acid is a key intermediate for preparing N-[[6-(lower alkoxy)-5-(trifluoromethyl)-1-naphthalenyl]thioxomethyl]-N-(lower alkyl)glycine derivatives of the formula ##STR1## in which R.sup.I and R.sup.II are the same or different lower alkyls. The latter derivatives are aldose reductase inhibitors and are useful for treating diabetic complications; for example, neuropathy, nephropathy, retinopathy, cataracts and atherosclerosis.
A process for preparing the key intermediate, the transformation of the intermediate to the aldose reductase inhibitors and the use of the inhibitors for treating diabetic complications are described in copending U.S. patent application Ser. No. 321,306, now U.S. Pat. No. 4,439,617 of K. Sestanj et al., filed on the same data hereas, the pertinent portions of which are herein incorporated by reference.
The process for the key intermediate in the copending application is exemplified as follows: 6-methoxy-1-naphthalenecarboxylic acid methyl ester is reacted with iodine and iodic acid in the presence of 98% sulfuric acid to give 5-iodo-6-methoxy-1-naphthalenecarboxylic acid methyl ester, which in turn is reacted with trifluoromethyl iodide and copper powder in a stainless steel autoclave to give 6-methoxy-5-(trifluoromethyl)-1-naphthalenecarboxylic acid methyl ester. Hydrolysis of the latter compound with dilute aqueous sodium hydroxide gives 6-methoxy-5-(trifluoromethyl)-1-naphthalenecarboxylic acid, one of the key intermediate noted hereinbefore. The latter compound also can be named 5-(trifluoromethyl)-6-methoxy-1-naphthalenecarboxylic acid.
Our novel process for preparing the key intermediate, although having more steps, is more efficient and less expensive than the process exemplified in the previous paragraph. More explicitly, the present process allows at least a doubling of the yield of the key intermediate. Furthermore, the process allows at least a ten-fold reduction in the cost of preparing the intermediate; a major contributing factor to the cost reduction being the use of trifluoroacetic acid, an inexpensive source for the trifluoromethyl group, rather than trifluoromethyl iodide, an expensive and more noxious reagent. Still furthermore, the present process does away with the need for high pressure equipment. All these advantages serve to make the present process a much more attractive commercial process than the process of the copending application.
The transformation of the key intermediate to the aldose reductase inhibitors, as disclosed in the copending application, is accomplished by coupling an activated ester of the key intermediate with the appropriate glycine ester to obtain the corresponding N-[(1-naphthalenyl)carbonyl]glycine ester; reacting the latter compound with phosphorus pentasulfide to obtain the corresponding N[(1-naphthalenyl)thioxomethyl]glycine ester; and then hydrolyzing the lastnamed compound to obtain the desired N-[[6-(lower alkoxy)-5-(trifluoromethyl)-1-naphthalenyl]thioxomethyl]-N-(lower alkyl)glycine. Optionally, the order of the last two steps can be reversed.